Reagent store

ABSTRACT

An automated analyzer with an on-board fridge for long-term cooling of reagents, and a method for isolating and analyzing an analyte comprising long-term cooling of reagents.

CROSS-REFERENCES TO RELATED APPLICATIONS

The present application is a divisional of U.S. patent application Ser.No. 13/297,853, filed on Nov. 16, 2011, which claims the benefit ofpriority under 35 U.S.C. § 119 of EP10192034.6, filed Nov. 22, 2010, thecontents of which are incorporated by reference herein in theirentireties.

FIELD OF THE INVENTION

The present invention relates to an automated analyzer and an automatedsystem for detecting or quantitating analytes and a method for detectingor quantitating an analyte in a sample.

BACKGROUND OF THE INVENTION

Automated analyzers are commonly used diagnosing conditions inindividuals, or for testing pools of samples from one or multipleindividuals. For analyzing an analyte in a sample, reagents arerequired. Such reagents have to be provided to the analyzer anddistributed within the analyzer. Therefore, reagents are commonly keptin reagent cassettes which can be loaded or unloaded into or from theanalyzer. Frequently, such reagents are temperature sensitive. In someanalyzers, reagents are only loaded for a single load and then manuallyretrieved and transferred into a refrigerator. Analyzers are also knownwith onboard cooled storage.

The present invention provides for improved automated analyzers, systemsand methods comprising cooled storage of reagents.

SUMMARY OF THE INVENTION

The present invention relates to an automated analyzer for isolatingand/or analyzing an analyte. The analyzer of the present inventioncomprises a unit for transferring a liquid. This unit comprises astation for presenting a reagent cassette to a pipetting device. Theanalyzer further comprises a unit for isolating said analyte.Furthermore, the analyzer comprises a closed reagent store for storingreagents. Such reagents preferably comprise reagents necessary forperforming the analysis. The closed reagent store comprises a coolingunit for active cooling. Furthermore, it comprises an internal storageand retrieval unit. In order to allow input and output of reagentcassettes, a closure is comprised in the closed reagent store. Theclosed reagent store also comprises an identification unit foridentifying the contents of a reagent cassette. For automated transportof the reagent cassettes between the closed reagent store to otherstations of the analyzer and back to the reagent store, the analyzeralso comprises a handler system for bidirectional transport of saidreagent cassette between said reagent store and said station forpresenting a reagent cassette

The present invention also relates to a method for providing reagents toan analytical system comprising the steps of:

-   -   loading reagent cassettes into a reagent store;    -   identifying said cassettes;    -   automatically transferring said cassettes into said reagent        store;    -   positioning said cassettes within said reagent store;    -   transferring instructions from a control unit to said reagent        store, wherein said instructions specify which cassettes are        required by the system;    -   providing said cassettes to a handler system;    -   transporting said cassettes with said handler system to a        station for presenting said cassettes to the system;    -   returning said cassette to said reagent store or transferring        said cassette to a waste station.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1A shows a workflow of reagent cassettes in analyzer comprisingreagent stores. FIG. 1B shows the workflow for further transport.

FIG. 2 shows a view of lower part of analyzer module with stacker andreagent store.

FIG. 3 shows a closed reagent store.

FIG. 4 shows a view of loading of reagent cassette into reagent store.

FIG. 5 shows a view of lower part of analyzer module with stackers andtemporary store.

FIG. 6 shows a view of outside of temporary store.

FIG. 7 shows a view of temporary store with open emergency door.

FIG. 8 shows a storage and retrieval system of temporary store.

FIG. 9 shows a storage and retrieval system of temporary store withreagent cassette.

FIG. 10 shows a first schematic view of analytical system.

FIG. 11 shows a second schematic view of analytical system.

FIG. 12 shows a third schematic view of analytical system.

DETAILED DESCRIPTION OF THE INVENTION The Reagent Store

The present invention relates to an automated analyzer for isolatingand/or analyzing an analyte.

The terms “analytical apparatus” (400) and “analyzer” (400) and“analytical instrument” (400) are used interchangeably. An analyticalsystem comprises an analyzer. An analyzer comprises one or more modulesor cells or units. Said modules or cells or units comprise stations forcarrying out the processing and/or analysis of an analyte.

The term “analyte” as used herein may be any type of biomolecule whichis of interest for detection, and the detection thereof is indicative ofa diagnostic status of an organism. The organism can be animal or, inone embodiment, human. Analytes may be proteins, polypeptides,antibodies or nucleic acids. In one embodiment, the analyte is a nucleicacid. The analyte may be present in a liquid sample, or it may bepresent as a solid sample affixed to a support. Solid samples mayinclude tissue.

The term “detecting” as used herein relates to qualitative measurementof an analyte.

The analyzer of the present invention comprises a unit for transferringa liquid.

The term “liquid” as used herein relates to any type of liquid which hasto be transferred during an analytical process. Thus, the term includesliquid samples. It also includes reagents or suspensions of reagents.

The unit for transferring liquids comprises a station for presenting areagent cassette to a pipetting device. In one embodiment, said unit isa unit or cell or module in which reagents are transferred from saidreagent cassette to at least one receptacle. In one embodiment, saidunit comprises a pipetting device for transferring samples from a samplevessel to at least one receptacle, and for transferring control reagentsto said at least one receptacle. Embodiments of pipetting devices,reagent cassettes, receptacles and control reagents are furtherdescribed herein. In one embodiment, said unit for transferring liquidsis a unit for preparing a reaction mixture. In such a unit, reagents areadded to an analyte prior to reaction. A reagent cassette can refer to acontainer comprising a liquid or suspension of reagents. Or a reagentcassette can be a holder for holding containers comprising a liquid or asuspension of reagents.

In one embodiment, the analyzer further comprises a unit for isolatingsaid analyte. Said unit for isolating said analyte and said unit fortransferring liquids may be located on a processing deck, and saidclosed reagent store may located below said processing deck. This hasthe advantage that space can be saved and the footprint of the analyzercan be significantly reduced. One embodiment is also comprised whereinthe unit for transferring liquids and the unit for isolating saidanalyte are merged into one unit.

In a further embodiment, the analyzer additionally comprises a unit forreacting said analyte to obtain a detectable signal. In an embodiment,said unit for reacting said analyte to obtain a detectable signal alsocomprises a detection unit. In another embodiment, said analyzeradditionally comprises a separate detection unit.

The term “processing deck” as used herein relates to a deck on whichsamples are processed. The processing deck may be one deck on which allstations necessary for processing are located. In a system comprisingmore than one module, the term “processing deck” includes all the deckswithin the different modules which comprise stations for processing asample. Thus, the term “processing deck” may also include the differentdecks in different modules of an analyzer.

In another embodiment, said unit for transferring liquids comprises aseparation station for isolating and purifying an analyte. In oneembodiment, the station for presenting a reagent cassette to a pipettingdevice is also disposed on said processing deck. In one embodiment, theclosed reagent store is disposed at a lower level, most preferably belowsaid processing deck. Thus, in one embodiment, the closed reagent storeand the station for presenting a reagent cassette to a pipetting deviceare separate. One advantage is that the space of the analyzer can beused in an optimal way by also using space underneath the processingdeck.

Furthermore, the analyzer comprises a closed reagent store for storingreagent cassettes. A closed reagent store is understood to relate to anincubator with a casing, wherein said casing is insulated from theenvironment and comprises a closure which allows opening and closing theincubator to add or retrieve reagent cassettes. Embodiments of closuresare doors or shutters or, in one embodiment, a drawer. Said reagentstore may additionally be suitable for storing other containerscomprising reagents.

Reagents comprise reagents necessary for performing the analysis.Reagents necessary for performing the analysis of analytes includereagents for sample preparation, control reagents, reagents for reactingwith the analyte to obtain a detectable signal, and/or reagentsnecessary for detecting the analyte. Such reagents may include reagentsfor isolating an analyte and/or reagents for processing a sample and/orreagents for reacting with an analyte to obtain a detectable signaland/or washing reagents and/or diluents.

The closed reagent store comprises a cooling unit for active cooling.The term “active cooling” is understood to mean that the incubator iskept within a predefined range of temperatures. A range of temperaturesis between −4° C., or −2° or 0° C. or 2° C. to 10° C., or 8° C. or 6° C.or 4° C.

Furthermore, it comprises an internal storage and retrieval unit. Theinternal storage and retrieval system comprises a transport mechanism,in one embodiment an elevator, for transporting a reagent cassette intothe reagent store, and storage positions, at least one turntable which,in one embodiment comprises centering blocks for positioning reagentcassettes. This allows for efficient internal storage and retrieval. Inone embodiment, the elevator comprises a Y-handler.

In order to allow input and output of reagent cassettes, a closure iscomprised in the closed reagent store.

The closed reagent store also comprises an identification unit foridentifying the contents of a reagent cassette.

For automated transport of the reagent cassettes between the closedreagent store to other stations of the analyzer and back to the reagentstore, the analyzer also comprises a transport system for bidirectionaltransport of said reagent cassette between said reagent store and saidstation for presenting a reagent cassette. Said system for bidirectionaltransport may comprise conveyors. In one embodiment, said transportsystem comprises at least one handler. In one embodiment, said handlersystem comprises at least two, or at least three handlers. One advantageof a handler system is that the closed reagent store can be locatedunderneath the processing deck.

Handlers and pipetting devices are well known in the art.

In one embodiment of the analyzer described herein, the analyzercomprises a control unit for transferring instructions to said closedreagent store, wherein said instructions specify the reagent cassetterequired by the system. Such control units may comprise processors andare known to the skilled person.

In one embodiment, the store and a temporary store are comprised on thesame module of an analyzer. In another embodiment, they are comprised ondifferent modules of an analyzer. In one embodiment, the analyzer is aself-contained analyzer with comprising stations within an open spacedevoid of any spatial separation.

The present invention also relates to a method of providing reagents toan analytical system comprising the steps of:

-   -   loading reagent cassettes onto a loading interface of a reagent        store;    -   identifying said reagent cassettes;    -   transferring said reagent cassettes into said reagent store;    -   positioning said reagent cassettes within said reagent store;    -   transferring instructions from a control unit to said reagent        store, wherein said instructions specify which reagent cassettes        are required by the system;    -   providing a reagent cassette to a transport system;    -   transporting said reagent cassette with said transport system to        a station for presenting said reagent cassette to a pipetting        device;    -   returning said reagent cassette to said reagent store or        transferring said reagent cassette to a waste station.

This method allows for returning partly used reagent cassettes to thecooled reagent store until further use. The life time of the reagentscan, thus, be prolonged, and reagents in a cassette can be used untilthe cassette is empty.

A loading interface is an interface associated with the closure hereindescribed which receives the reagent cassettes loaded by the operator, apreferred embodiment is the drawer herein described. In one embodiment,the operator manually loads the reagent cassettes into the drawer of theclosed reagent store. The drawer then automatically closes. The reagentcassettes are identified. In one embodiment, all steps after loading andbefore retrieval of reagent cassettes are automated.

In one embodiment of the method described herein, the reagent store is aclosed reagent store as described herein. Thus, said closed reagentstore is preferably cooled by an active cooling unit. In one embodiment,said positioning of said cassettes within said store and said providingof said cassettes is performed by an internal storage and retrievalunit.

In one embodiment of the method herein described, said reagent cassettescomprise at least one tag for reading and writing information. In oneembodiment, said method comprises storing onboard time on said tag. Inone embodiment, said storing of onboard time on said tag is done whenproviding said cassettes from said store to said handler system. In oneembodiment, said storing of onboard time comprises writing of a timestamp on said tag. Thus, in one embodiment, the method additionallycomprises determining and storing onboard time. Said determining andstoring onboard time is triggered when providing said reagent cassettefrom said store to said transport system. Said storing of onboard timemay be done with a decremental counter before returning said reagentcassette to said reagent store. Further embodiments are describedherein.

Thus, in one embodiment, said storing of onboard time comprises storingof onboard time with a counter. The counter may be a decrementingcounter. The speed of the decrementing counter is increased withincreased temperature. Thus, the speed of the decrementing counter isrelated, or is proportional to the difference between the temperature ofthe area of the presence of the reagent cassette and the reagent storefor long term storage. For the embodiment of the onboard time stamp,said time stamp is then compared with the actual time, an on-board timeis calculated based on said time stamp and the actual time, and acumulated onboard time is calculated and written on said tag beforereturning said cassette to said reagent store.

It is understood that whenever a process step is described herein whichrelates to writing an onboard time stamp to track onboard time, the sameprocess step can be replaced with determining onboard time using acounter, in one embodiment a decremental counter. An incremental counteris an alternative for counting onboard time. The lifetime of thereagents can, thus, be monitored and reagent use can be optimized.

The term “actual time” is understood to be the time when the respectiveprocess step is carried out.

Once reagents are presented to a pipetting device, said reagents aretransferred from said reagent cassette held in said station forpresenting said reagent cassette to at least one receptacle by apipetting device.

One embodiment of a workflow for the method herein described isdescribed in more detail in FIG. 1. Reagent cassettes comprise a tag forstoring information. Said information comprises information abouton-board time, in one embodiment, on-board time in different temperaturecompartments. The tag is an RFID tag. Reagent cassettes are loaded ontothe analyzer and stored in the reagent store described herein. A loadingflag is written onto the tag upon loading to store the loading date. Thecontrol system stores information on the type of reagent or reagentsstored in a reagent cassette and the location of the reagent cassettewithin the store. Upon receipt of information regarding reagents whichare required by the analytical system, the handler system retrieves andtransports the required cassette or cassettes to a station forpresenting a reagent cassette to the analyzer. A counter on the tag isnow triggered to decrementally count during time spent outside thereagent store. Alternatively, an onboard time stamp may be written ontothe tag. The reagent cassette is now transported either to a station forpresenting a reagent cassette to a pipetting device or to the temporaryreagent store herein described. If the reagent cassette is transportedto a station for presenting a reagent cassette to a pipetting device,the reagent cassette is either returned to the reagent store after use,or is transferred to a waste station. If the reagent cassette istransferred back to the reagent store, an onboard time stamp may bewritten on the tag. The process may then be repeated.

If the reagent cassette is transported to the temporary store, anonboard time stamp may be written onto the tag before placing thereagent cassette in the temporary store, if a time stamp is used tomonitor on-board time. With the counter, the decremental counting occursaccording to the temperature in the temporary store. The location of thecassette in the temporary store is stored by the control system. If thesystem requires reagents, the corresponding reagent cassette istransferred to a station for presenting a reagent cassette to apipetting device. The advantage of the temporary store is that a reagentcassette can be presented to the pipetting device very quickly. Whilethe reagent cassette is located on the station for presenting a reagentcassette, the counter counts faster than in the temporary store if thetemperature on the station for presenting a reagent cassette is higherthan in the temporary store. The reagent cassette may be returned to thetemporary store for re-use or to the reagent store for long timestorage. An on-board time stamp is written onto the tag prior to storagein the reagent store. An onboard time counter is updated. The reagentcassette is then stored in the reagent store until it is required again.

If total onboard time exceeds a preset value, if reagent levels in thereagent cassette are too low or if the reagent cassette is erroneous, itis transported to a waste station or to an input/output position formanual removal.

The analytical system herein described, thus, comprises areading/writing device (1160) (as shown in FIG. 11).

Also within the scope of the present invention are analyzers and systemsfor isolating and/or analyzing an analyte as described herein, whichcomprise a reagent store as described herein.

Furthermore, a method for analyzing an analyte in a system comprising areagent store as described herein is also within the scope of thepresent invention.

A method for isolating and analyzing an analyte that may be present in aliquid sample is disclosed. Said method comprises the automated steps of

-   -   a) transferring said liquid sample from a sample vessel to a        processing vessel with a pipette tip;    -   b) combining together a solid support material and said liquid        sample in a well of said processing vessel for a period of time        and under conditions sufficient to permit said analyte to be        immobilized on the solid support material;    -   c) isolating the solid support material from other material        present in the liquid sample in a separation station;    -   d) and purifying the analyte in the separation station by        separating the liquid sample from the solid support material and        washing the materials one or more times with a wash buffer.

In one embodiment, the processing vessel may comprise more than onereceptacle. In one embodiment, the processing vessel is a multiwellplate. The method, in one embodiment, additionally comprises the step of

-   -   e) reacting said purified analyte with reagents necessary to        obtain a detectable signal.

The term “receptacle” as used herein relates to a single vessel (ortube) or to a tube comprised in a multi-tube unit, or to a well (orvessel) of a multiwell plate.

The term “vessel” is understood to mean a single vessel or a singlevessel in a multi-tube unit, a multiwell plate or a multi-tube unit or awell of a multiwell plate.

In one embodiment, the reacting comprises generating a detectablesignal. Furthermore, the method may additionally comprise the step ofdetecting a detectable signal.

The term “reacting” as used herein relates to any type of chemicalreaction of the analyte with reagents that is necessary to obtain adetectable signal. In one embodiment, said reacting comprisesamplification. Amplification may be understood as any type ofenhancement of a signal. Thus, amplification can be a conversion of amolecule by an enzyme, wherein said enzyme is coupled or bound to theanalyte, leading to a detectable signal, wherein more signal moleculesare formed than analyte molecules are present. One such non-limitingexample is a formation of a chemiluminescent dye, e.g. using ECL. Theterm amplification further relates to nucleic acid amplification, if theanalyte is a nucleic acid. This includes both linear, isothermal andexponential amplifications. Non-limiting examples of nucleic acidamplification methods are TMA, SDA, NASBA, PCR, including real-time PCR.Such methods are well known to the skilled person.

The term “solid support” as used herein relates to any type of solidsupport to which the analyte is capable of binding, either directly andnon-specifically by adsorption, or indirectly and specifically. Indirectbinding may be binding of an analyte to an antibody immobilized on thesolid support, or binding of a tag to a tag binding compound, e.g.binding of 6×His tags to Ni-chelate. When the analyte is a nucleic acid,such indirect binding may be by binding to a capture nucleic acid probewhich is homologuous to a target sequence of the nucleic acid ofinterest. Thus, using capture probes attached on a solid support, atarget analyte, or a target nucleic acid, can be separated fromnon-target material, or non-target nucleic acid. Such a capture probe isimmobilized on the solid support. Solid support material may be apolymer, or a composition of polymers. Other types of solid supportmaterial include magnetic silica particles, metal particles etc.

Non-specific binding of nucleic acid to silica particles occurs in thepresence of chaotropic compounds. Such binding may also be referred toas direct binding, as opposed to the indirect binding described herein.In one embodiment, the solid supports silica particles which comprise amagnetic or magnetizable material.

FIG. 2 shows the lower part (1100) of a module of an analyzer. On top isa processing plate (1101). Lower part (1100) comprises a frame (1110).The processing plate comprises a station (1102) for presenting a reagentcassette (1122). The housing of a stacker unit is also shown (1103). Thestacker unit further comprises a reagent drawer (1104) into whichreagent cassettes are loaded. An elevator (1105) then moves the cassetteto a level where it can be transferred into the reagent store (1106).The elevator comprises a Y handler (1105) and a Z-axis (1108). Thespindle (1109) of the elevator (1105) is also shown. Also visible is anarrangement (1111) for opening a back door of the store (1106). Thestore (1106) and the back door (1112) as well as the cooling unit (1115)is shown in FIG. 3.

FIG. 4 shows the reagent cassette drawer (1104), the open front door(1125) of the reagent store (1106) and a reagent cassette (1122)comprising reagent inserts (1130). The reagent cassette (1122) ispositioned on the Y handler (1105). The Y handler (1105) is about toplace the reagent cassette (1102) into the store (1106). The interior ofthe store (1106) comprises turn tables (1113) on which reagent cassettes(1122) are placed and can be positioned. The turn tables (1113) comprisecentering blocks (1114) in which the cassettes (1122) are positioned. Apreferred number of centering blocks (1114) is 4 blocks (1114).

An automated analyzer (400) for use in performing a nucleic acid basedamplification reaction is shown in FIG. 12. Said analyzer comprises aplurality of modules (401, 402, 403). One module is a processing moduledisposed at a first location within the analyzer constructed andarranged to separate a nucleic acid from other material in a sample.Said processing module comprises a separation device as hereindescribed. The analyzer further comprises an amplification moduledisposed and arranged at a second location within the analyzer. Theamplification module comprises a temperature-controlled incubator forincubating the contents of at least one receptacle, preferably of amultiwell plate comprising the separated nucleic acid and one or moreamplification reagents for producing an amplification product indicativeof the target nucleic acid in the sample.

In one embodiment, an analytical system (440) for processing an analytecomprises, according to FIG. 10,

-   -   a) a first position comprising first receptacles (1001) in        linear arrangement comprising liquid samples (1010), a        processing plate (101) comprising receptacles (103) in n×m        arrangement for holding a liquid sample (1011), a first        pipetting device (700) comprising at least two pipetting units        (702) in linear arrangement, wherein said pipetting units (702)        are coupled to pipette tips (3, 4), and a tip rack (70)        comprising pipette tips (3, 4) in an ax(n×m) arrangement;    -   b) a second position comprising a holder (201, 128) for said        processing plate (101), a holder (470) for said tip rack (70)        and a second pipetting device (35), said second pipetting device        (35) comprising pipetting units (702) in an n×m arrangement for        coupling to pipette tips (3, 4) (FIG. 10). The term “holder” as        used herein relates to any arrangement capable of receiving a        rack or a processing plate.

The advantages of the analytical system (440) of the present inventionare as described herein for the method of the present invention.

The advantages of the analytical system (440) are as described herein.

In one embodiment, the position of said pipetting units (702) of thefirst pipetting device (700) are variable. Embodiments of said firstpipetting device (700) are described herein.

In one embodiment, the tip rack (70) comprises pipette tips (3, 4) in anax(n×m) arrangement. In one embodiment, a first type (4) and a secondtype (3) of pipette tips are comprised in the tip rack (70). In thisembodiment, the first type of pipette tips (4) is arranged in an n×marrangement, and the second type of pipette tips (3) is arranged in then×m arrangement. In one embodiment, the first type of pipette tips (4)has a different volume than the second type of pipette tips (3). In oneembodiment, the volume of the first type of pipette tips (4) is morethan 500 ul, and the volume of the second type of pipette tips (3) isless than 500 ul. In this embodiment, a=2. However, embodiments of theinvention with more than two types of pipette tips, and thus a>2 arealso included in the present invention.

In one aspect, the analytical system (440) of the present inventioncomprises a control unit (1006) for allocating sample types andindividual tests to individual positions of said processing plate (101).Preferably, said positions are separate cells (401, 402).

In one aspect of the invention, the system additionally comprises atransfer system (480) for transferring said process plate (101) and saidrack (70) between first (402) and second (401) positions. Embodiments ofsaid transfer system (480) are conveyor belts or, one or more handler.

Furthermore, said pipette units of said second pipetting device (35) areengaged to pipette tips (3, 4) which were used in the first position(402).

One embodiment of the system (440) described herein additionallycomprises a third station (403) comprising a temperature-controlledincubator for incubating said analyte with reagents necessary to obtaina detectable signal. A further embodiment of third station (403) is aamplification station comprising a thermoblock. More optimal control ofthe allocation of samples and tests to the n×m arrangement is achievedwith a first processor (1004) which is comprised in said first position(402) to which said control unit (1006) transfers instructions forallocating sample types and individual tests to specific positions inthe n×m arrangement of vessels (103) of the process plate (101), and asecond processor (1005) which is comprised in said second position (401)to which said control unit (1006) transfers instructions for allocatingsample types and individual tests to specific positions in the n×marrangement of vessels (103) of the process plate.

In one embodiment, the system additionally comprises a first processorlocated in said first position, and a second processor located in saidsecond position.

In one embodiment, said first processor (1004) controls said firstpipetting device (700) and said second processor (1005) controls saidsecond pipetting device (35).

Temporary Store

The present disclosure also relates to an automated analyzer forisolating and/or analyzing an analyte which comprises a unit fortransferring a liquid comprising a station for presenting at least onereagent cassette to a pipetting device. The analyzer additionallycomprises a unit for analyzing an analyte. Furthermore, the analyzeralso comprises a unit for temporary storage of at least one reagentcassette comprising reagents necessary to isolate and/or analyze saidanalyte.

The temporary storage makes it possible to store reagent cassettes whilethey are needed by the analyzer, and to remove them when they are notneeded any longer.

In one embodiment, the unit for transferring a liquid additionallycomprises at least one station for isolating an analyte. Embodiments forsaid station for isolating an analyte are described herein. The unit fortransferring a liquid and the unit for temporary storage of at least onereagent cassette preferably overlap at least partially. In oneembodiment, said station for presenting at least one reagent cassette toa pipetting device is located within said overlapping area. It isunderstood that said unit for transferring a liquid comprises at leastone pipetting device. In one embodiment, the station for presenting atleast one reagent cassette to a pipetting device is located outside thetemporary store. In one embodiment, the overlapping area comprises anelevator plate.

In a further aspect of the present disclosure, the analyzer additionallycomprises a unit for transferring a sample comprising an analyte from afirst receptacle to a second receptacle. In one aspect of the presentdisclosure, the analyzer additionally comprises a closed reagent store.

In an embodiment of the analyzer, the unit for temporary storagecomprises a cooling unit. Further embodiments of said temporary storageunit are disclosed herein.

Embodiments of said closed reagent store are described herein. Thecooling unit of said closed reagent store is set to keep the insidetemperature of the closed reagent store between a lower specifiedtemperature and an upper specified temperature. Embodiments of saidtemperatures are disclosed herein.

The closed reagent store is particularly useful since it provides forlong term storage of temperature sensitive reagents. Such reagentsinclude, but are not limited to, reagents comprising enzymes, such aspolymerases for amplifying nucleic acids, or enzymes for colorreactions. The combination of a reagent store for long term storage ofreagents and a temporary store according to the present disclosure isparticularly advantageous in an analytical system. This reduces the timeduring which a reagent cassette and its contents are exposed totemperatures above the storage temperatures to a minimum. In such ananalyzer and system, reagent cassettes with reagents can be loaded lessfrequently, thus increasing walk-away time for the operator. Bytransferring reagent cassettes from the reagent store to the temporarystore, the reagent cassettes are presented to the pipetting device morequickly than if they had to be transferred directly from the reagentstore. It allows for placing the reagent store in an area of theanalyzer where space is readily available. The dimensions of thetemporary storage unit can be reduced to the space necessary to storereagent cassettes required for a current run, thus making it possible toplace it in close proximity of the unit for transferring liquids whileminimizing the space occupied by the temporary storage unit. This setupis particularly advantageous for a quick and timely presentation of thereagent cassettes to the pipetting device when the respective reagentsare needed.

The temporary store has further advantages. In one aspect, it comprisesa closed cooling area with a cooling unit. In one aspect, said coolingis an active cooling unit. The cooling unit is set to keep thetemperature below a threshold temperature. In one embodiment, thethreshold temperature is 40° C., more preferably 35° C. or 30° C., mostpreferably 28° C. The cooling unit only has to operate to keep thetemperature below such threshold. Thus, less energy is required than forthe reagent store. On the other hand, the lifetime of the reagents isoptimized because they only are kept in the temporary store as long asthey are needed, and are then returned to the reagent store forlong-term storage. The exposure to elevated temperature is thusminimized while quick and timely presentation of the reagent cassettesto the pipetting device is maintained.

Embodiments of the closed reagent store are described herein.

In one preferred aspect of the invention, the analyzer additionallycomprises a handler system for bidirectional transport of said reagentcassette between said closed reagent store and said station forpresenting a reagent cassette. Further preferred embodiments aredescribed herein.

The present invention also relates to a method of presenting a reagentcassette comprising reagents for analyzing an analyte to a pipettingdevice within an automated analyzer, comprising the steps of:

-   -   transferring a reagent cassette stored in a closed reagent store        with active cooling to a temporary storage unit;    -   holding said reagent cassette in said temporary storage unit        until it is needed by the analyzer;    -   transferring said reagent cassette from said temporary storage        unit to a station for presenting said reagent cassette to said        pipetting device, wherein said station for presenting said at        least one reagent cassette is located outside the temporary        storage;    -   transferring said reagent cassette back to said temporary        storage unit when pipetting of the reagent is finished.

Such a method is advantageous because the reagent cassettes comprisingreagents are exposed to higher temperature areas within the analyzeronly while they are needed, while they can be mobilized quickly whenneeded for pipetting.

In one aspect, steps b) to d) are repeated at least once. In oneembodiment, said reagent cassette is transferred from said closedreagent store to said temporary storage unit with a handler system.

In one embodiment, said reagent cassette is transferred from said closedreagent store to a first position with a first handler, and from saidfirst position to the temporary store with a second handler.

In one aspect, the reagent cassettes comprise a tag for storinginformation, wherein information of onboard time in the automatedanalyzer is stored on said tag.

In a preferred embodiment, the method herein described additionallycomprises the step of transferring said reagent cassette to said closedreagent store for long term storage until the reagent comprised in saidreagent cassette is required for a new test, if said reagent cassette isnot empty, or transferring said reagent cassette to a consumable wastestation. The reagent cassettes are additionally preferably manuallyloaded into a drawer of said closed reagent store, wherein said reagentcassette is automatically transferred within said closed reagent store.

In one embodiment, said reagent cassette in the temporary store istransferred to the station for presenting the reagent cassette to apipetting device by an elevator.

Further preferred embodiments are as described herein.

Exemplary embodiments of the analyzer of the present invention and itscomponents, in particular the temporary storage unit, are shown herein.

In one embodiment, the method herein described additionally comprisesthe step of transferring said reagent cassette to said closed reagentstore for long term storage until the reagent comprised in said reagentcassette is required for a new test, if said reagent cassette is notempty, or transferring said reagent cassette to a consumable wastestation. The reagent cassettes are additionally manually loaded into adrawer of said closed reagent store, wherein said reagent cassette isautomatically transferred within said closed reagent store.

Further embodiments are as described herein.

Embodiments of the analyzer as disclosed herein and its components, inparticular the temporary storage unit, are shown herein.

FIG. 5 shows a lower part (1149) of a module of an analyzer, which, inone embodiment is a processing module (402) (FIG. 10). The top of thelower part (1149) is a processing plate (1150). The lower part furthercomprises a frame (1157). A stacker (1151) is also shown. The processingplate (1150) comprises a station (1156) for presenting a reagentcassette (1122) (shown e.g. in FIG. 4) to a pipetting device and anelevator plate (1152) inside said station for presenting a reagentcassette (1122) to a pipetting device. The reagent cassette (1122)comprises a tag for storing information (1160). The elevator plate(1152) can be moved in Z direction. Also shown is the temporary store(1153). FIG. 6 shows a temporary store (1153), the station (1156) forpresenting a reagent cassette to a pipetting device, and an emergencydoor (1154) for unloading the store and an air outlet (1147). FIG. 7shows features as FIG. 6, except that the emergency door (1154) isremoved and a holding unit (1155) for holding cassettes inside thetemporary store (1153) and a cassette (1122) can be seen. The inside ofthe temporary store is shown in FIGS. 8 and 9. FIG. 8 shows a frame(1158), holding unit (1155), reagent cassette (1122) held in a holdingunit, a station (1156) for presenting a reagent cassette (1122) and anelevator plate (1152). In particular, FIG. 9 also shows the elevator(1159).

Analytical Apparatus and Method for Isolating and Analyzing an Analyte

A method for isolating and analyzing an that may be present in a fluidsample is analyte is disclosed. Said method comprises the automatedsteps of

-   -   f) transferring said fluid sample from a sample vessel to a        processing vessel with a pipette tip;    -   g) combining together a solid support material and said fluid        sample in a well of said processing vessel for a period of time        and under conditions sufficient to permit said analyte to be        immobilized on the solid support material;    -   h) isolating the solid support material from other material        present in the fluid sample in a separation station;    -   i) and purifying the analyte in the separation station by        separating the fluid sample from the solid support material and        washing the materials one or more times with a wash buffer.

In one aspect, said pipette tip used in step a) is re-used after stepa).

In the method herein described, step a) may further comprise

-   -   a1) engaging pipette tips of a first type which are held in a        rack in a first position with a first process head;    -   a2) transferring said fluid sample from a sample vessel to a        processing vessel with pipette tips of a first type engaged to a        first process head;    -   a3) placing said pipette tips in said rack and disengaging said        pipette tips from said process head;    -   a4) transporting said rack comprising said pipette tips and said        processing vessel to second positions;    -   a5) engaging said pipette tips of a first type which are held in        said rack with a second process head in said second position.

In one embodiment, the processing vessel may comprise more than onereceptacle. In one aspect, the processing vessel is a multiwell plate.The method preferably additionally comprises the step of

-   -   j) reacting said purified analyte with reagents necessary to        obtain a detectable signal.

Re-use of pipette tips leads to a reduction of disposable consumablesused in the analytical method and to cost reductions. In one embodiment,the washing in step d) comprises aspirating and dispensing the washingbuffer with a process head engaged to pipette tips.

In one embodiment, the reacting comprises generating a detectablesignal. In one aspect, the method additionally comprises the step ofdetecting a detectable signal.

In one embodiment of the method herein described, the transporting ofsaid rack comprising said pipette tips and said processing vessel to asecond position occurs between a separate first cell of an analyticalinstrument and a separate second cell, which may be a processing cell,of said analytical system. In one aspect, the rack comprises independentchambers to accommodate pipette tips.

In one embodiment, the first type of pipette tips is re-used for thewashing in step d).

In one embodiment, the rack additionally comprises a second type ofpipette tips. Further, in one aspect the method as herein describedcomprises, between step d) and e), the analyte is eluted from themagnetic particles. One embodiment comprises the transfer of the analytefrom said processing vessel, which is preferably a multiwell plate, to areaction vessel, which is preferably a multiwell plate, with said secondtype of pipette tips.

The present disclosure describes an analytical system for isolating ananalyte, said system comprising

-   -   a) a first position comprising a first receptacle holding a        liquid sample comprising an analyte, a second receptacle for        holding a liquid sample, a rack holding pipette tips, and a        first process head for transferring a liquid sample from the        first receptacle to a second receptacle,    -   b) a second position comprising a station for receiving said        second receptacle, and a rack holding station for receiving said        rack,    -   c) a transfer system for transferring the second receptacle and        the rack holding pipette tips between the first position and the        second position.

In one embodiment, the positions are separate cells. The racktransferred by said transfer system comprises pipette tips which wereused in the first position. In one embodiment, the first receptacle is asample vessel and the second receptacle is a processing vessel. In oneaspect, the processing vessel is a multiwell vessel. Embodiments of saidstations are described herein.

In the analytical system herein described, the transport systempreferably transfers the receptacle and the rack from the first positionto the second separate position. In one aspect, the second separateposition comprises a magnetic separation station. The analytical systemadditionally comprises, in another aspect, an amplification station.

The transport system of one embodiment of the system comprises a handlerconstructed and arranged to grip and transport said rack and saidprocessing vessel from a first to a second location within the system.Handlers are known to the skilled person.

In one embodiment, the system is fully automated.

The present disclosure also relates to an automated analyzer forisolating and analyzing an analyte comprising a plurality of stationsdisposed within said analyzer. The plurality of stations comprises asample dispensing station disposed in a first location. In one aspect,said sample dispensing station is constructed and arranged to dispenseliquid sample comprising an analyte from a sample vessel to a processingvessel with pipette tips held in a rack. In one aspect, sampledispensing stations are stations comprising a sample vessel, aprocessing vessel and a liquid dispensing unit. Said liquid dispensingunit may be a process device.

The automated analyzer further comprises a separation station disposedin a second location. In one aspect, said separation station isconstructed and arranged to receive said processing vessel holding saidliquid sample and said rack holding pipette tips used in the sampledispensing station and to separate an analyte from other materialpresent in the liquid sample. Another embodiment of a separation stationis a separation station comprising movable magnets.

The automated analyzer further comprises a reaction station disposed ina third location, wherein said reaction station is constructed andarranged to analyze said analyte to obtain a detectable signal. Anotherembodiment of a reaction station is a station comprising an incubator.In one aspect, said incubator is a temperature-controlled incubator. Inanother aspect, said incubator is held at one constant temperature.Another embodiment of an incubator is a thermocycler block. In oneaspect, a detector for detecting the detectable signal is integrallyconnected to the reaction station, or to the incubator. One embodimentof a detector comprises a nucleic acid quantification system forperiodic measurement and quantification. In one aspect, the detectoradditionally comprises a nucleic acid detection system which detects thesignal and ascertains the presence or absence of the nucleic acid in thereaction receptacle based upon whether or not a signal above a thresholdlevel is detected.

Alternatively, the automated analyzer additionally comprises a detectingstation. The automated analyzer further comprises a transport mechanism.Said transport mechanism comprises a handler for handling consumables.Said handler preferably transports a consumable between stations. In oneembodiment, said transport mechanism is constructed and arranged totransport said sample vessel and said rack from said sample dispensingstation to said separation station. Further embodiments of the automatedanalyzer of the present disclosure are individual or combined featuresdisclosed herein.

In one embodiment, the analytical apparatus (400) of the presentdisclosure comprises at least one module (401) for processing ananalyte, said processing comprising pipetting of a liquid. Theprocessing module (401) comprises:

-   -   a) a process head (35) for engaging with pipette tips (3, 4),        said process head (35) comprising positioning elements (36)        arranged in the lower surface (61) of said process head (35),    -   b) a tip rack (60, 70) holding pipette tips (3, 4), wherein said        tip rack (60, 70) comprises positioning elements (31, 32, 33,        34) capable of engaging mechanically with the positioning        elements (36) on the process head (35).

In one embodiment of the analytical apparatus (400) herein described,said processing module (401) is a module for isolation and purificationof an analyte. Therefore, the term “processing” as used herein isunderstood to relate to isolation and/or separation and/or captureand/or purification of an analyte. In one aspect, said apparatus (400)comprises a module for preparing samples for processing (402). In oneaspect, said apparatus (400) comprises a module for amplification ofsaid analyte (403). In one embodiment, said apparatus additionallycomprises a module (404) for transferring amplification reagents from astorage receptacle to a receptacle comprising a purified analyte.Further embodiments of said apparatus are as herein and hereindescribed.

The present disclosure also relates to an automated analyzer (400) foruse in performing a nucleic acid based amplification reaction, saidanalyzer comprising a plurality of modules (401, 402, 403). One moduleis a processing module disposed at a first location within the analyzerconstructed and arranged to separate a nucleic acid from other materialin a sample. Said processing module comprises a separation device asherein described. The analyzer further comprises an amplification moduledisposed and arranged at a second location within the analyzer. Theamplification module comprises a temperature-controlled incubator forincubating the contents of at least one receptacle, in one aspect of amultiwell plate comprising the separated nucleic acid and one or moreamplification reagents for producing an amplification product indicativeof the target nucleic acid in the sample.

The present disclosure also relates to an analytical system comprising aholding station and a multiwell plate set as described herein. In oneembodiment, said multiwell plate set is fixed in said holding station.In one embodiment, the multiwell plate comprises a base with a rim whichcomprises recesses, wherein a positioning and fixing element, in oneaspect a latch-clip (FIGS. 47a ) and b)), on said holding stationcontacts said recesses, wherein said contact exerts a downwards pressureon the base of the multiwell plate, thereby fixing the multiwell platein the holding station. Further embodiments of the analytical systemcomprise individual or combined features described herein.

The present disclosure also relates to an analytical instrumentcomprising:

-   -   a processing module for isolating and purifying an analyte        comprising a holding station (470) for holding a rack comprising        pipette tips, said rack comprising at least one recess located        on one side wall of the rack, and at least one recess located on        an opposite second side wall of said rack, wherein said holding        station comprises a fixing element, in one aspect a latch-clip        and wherein said fixing element, or a latch-clip interacts with        said recess by exerting a force against the bottom of said        recess; and    -   a module (403) for analyzing said purified analyte by reacting        said analyte with reagents necessary to obtain a detectable        signal.

The analytical instrument, in one aspect, additionally comprises aliquid handling module (404, 500). Further embodiments of the analyticalinstrument are described herein, either separately or as combinations ofembodiments. In one aspect, the analytical instrument according to thepresent disclosure preferably additionally comprises a sealing station(410). The sealing station (410) is located in the process module (401).

The term “module” and “cell” are used interchangeably herein.

While the foregoing invention has been described in some detail forpurposes of clarity and understanding, it will be clear to one skilledin the art from a reading of this disclosure that various changes inform and detail can be made without departing from the true scope of theinvention. For example, all the techniques and apparatus described abovecan be used in various combinations. All publications, patents, patentapplications, and/or other documents cited in this application areincorporated by reference in their entirety for all purposes to the sameextent as if each individual publication, patent, patent application,and/or other document were individually indicated to be incorporated byreference for all purposes.

What is claimed is:
 1. An automated analyzer for isolating and/oranalyzing an analyte comprising: a unit for transferring a liquidcomprising a station for presenting a reagent cassette to a pipettingdevice; a unit for isolating said analyte; a closed reagent store and atemporary store, each configured to store said reagent cassettecomprising reagents necessary for performing the analysis, each of saidclosed reagent store and said temporary store comprising: a cooling unitfor active cooling of said reagent store; an internal storage andretrieval system comprising a transport mechanism including an elevatorhaving a Y-handler and a Z-axis; a closure for input and output ofreagents; an identification unit configured to read and writeinformation to and from an RFID tag positioned on said reagent cassetteand thereby identify said reagent cassette, wherein said informationcomprises an on-board time stamp: a handler system for bidirectionaltransport of said reagent cassette between said reagent store, saidtemporary store, and said station for presenting a reagent cassette; anda control unit programmed to (i) determine a cumulated on-board time ofsaid reagent cassette in one or more of said temporary store, said unitfor transferring and said unit for isolating said analyte; (ii) removethe reagent cassette from the reagent store using the handler whichtriggers the identification unit to write an on-board time stamp to theRFID that corresponds to the time the reagent cassette is removed fromthe reagent store; (iii) compare said cumulated on-board time to apreset value stored to said control unit and determine whether saidcumulated on-board time exceeds said preset value: (iv) transferinstructions to said handler system to return said reagent cassette toone of said reagent store and said temporary store if said cumulated onboard time is less than said preset value or dispose of said reagentcassette if said cumulated on-board time exceeds said preset value: and(v) transfer instructions to one or more of said reagent store and saidtemporary store regarding reagent cassette requirements for saidanalyzer: wherein said unit for isolating said analyte and said unit fortransferring a liquid are located on a processing deck, and said closedreagent store is located below said processing deck.
 2. The analyzer ofclaim 1, wherein said unit for transferring a liquid comprises aseparation station for isolating and purifying an analyte.
 3. Theanalyzer of claim 1, wherein said handler system comprises at least twohandlers.
 4. The analyzer of claim 1, wherein the analyzer is configuredto return the reagent cassette to the reagent store when the on-boardtime is less than a preset value.
 5. The analyzer of claim 1, whereinthe analyzer is configured to transfer the reagent cassette to a wastestation when the on-board time exceeds a preset value.